CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity

Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2<sup>+</sup> (HER2<sup>+</sup>) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27<sup>+</sup> memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.

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Publication Details

Journal
Science Immunology
Published
2025-12-19
DOI
https://doi.org/10.1126/sciimmunol.adz2294
Primary Topic
Immunotherapy and Immune Responses
Type
article
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article

CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity

Jason McBane, Xingru Ma, Bin-Jin Hwang, Jun-Ping Wei et al.
Science Immunology
Immunotherapy and Immune Responses
article

CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity

Jason McBane, Xingru Ma, Bin-Jin Hwang, Jun-Ping Wei, Karrie Comatas, Gangjun Lei, H. Kim Lyerly, Erika J. Crosby, David T. Severson, Tibor Keler, Cong-Xiao Liu, Jesuchristopher Joseph, Li-Chung Tsao, Elishama Kanu, Zachary C. Hartman, Timothy N. Trotter, Michael A. Morse, Xiaoyi Yang, Ethan Agritelley, Tao Wang, Li-Zhen He, Bushanqing Liu, Amy Hobeika
article en

Abstract

Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2<sup>+</sup> (HER2<sup>+</sup>) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27<sup>+</sup> memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.

Science ImmunologyVol. 10(114)
Duke University (US), Celldex Therapeutics (United States) (US)
Openalex Percentile: Top 53%
Immunotherapy and Immune Responses
DOISourceOpenAlex
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